Chronic hypoxia (CH) occurs in many cardiopulmonary diseases and high altitude residency. This common clinical stress causes the remodeling, vasoconstriction and hypertension in the pulmonary artery (PA). These cellular responses primarily result from an increase in intracellular Ca concentration ([Ca2+]i, i.e., Ca2+ signaling) in PA smooth muscle cells (PASMCs). However, the underlying molecular mechanisms are not fully understood, and current therapeutic options for pulmonary hypertension (PH) are limited. Based on our preliminary data and previous publications, we propose a very innovative central hypothesis that CH causes Rieske iron-sulfur protein (RISP)-mediated mitochondrial reactive oxygen species (ROS) production, disrupts FK506 binding protein 12.6 (FKBP12.6)/ryanodine receptor-2 (RyR2) complex, causes RyR2 hyperfunction, increases Ca2+ release, activates calcineurin, cytoplasmic nuclear factor of activated T- cells (NFATc) and nuclear factor-kB (NFkB), and increases cyclin expression in PASMCs, leading to PA remodeling, contraction and hypertension. To test this exciting hypothesis, we will employ complementary, state-of-the-art laser scanning confocal microscopy, patch clamp recording, gene-manipulation, double immunofluorescence staining, florescent resonance energy transfer, and other approaches to address the following fundamental questions (Specific Aims): (1) is the FKBP12.6/RyR2 complex disrupted as a result of RISP-mediated mitochondrial ROS production in PASMCs from mice following CH; (2) does the disruption of the FKBP12.6/RyR2 complex mediate CH-induced PA remodeling, contraction and hypertension; and (3) is the role of FKBP12.6/RyR2 complex disruption in CH-induced responses in PAs mediated by the calcineurin-dependent, NF-kB/NFATc-mediated cyclin signaling axis? We fully believe that the findings from the proposed studies will greatly improve our current knowledge of the cellular molecular mechanisms for PA remodeling, constriction and hypertension, and help to fully understand what and how Ca2+ downstream signaling axis is in hypoxic. It is expected that the results may also aid in the creation of novel, specific and more effective therapeutic targets for the treatment of PAH and other relevant pulmonary vascular diseases, with a great potential for revolutionizing clinical practices.